Positive feedback loop between Sox2 and Sox6 inhibits neuronal differentiation in the developing central nervous system
Positive feedback loop between Sox2 and Sox6 inhibits neuronal differentiation in the developing central nervous system
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DOI：
10.1073/pnas.1308758111
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发表时间：
2014-02-18
影响因子：
11.1
通讯作者：
Kim, Jaesang
中科院分区：
文献类型：
--
作者：
Lee, Kyung Eun;Seo, Jihae;Kim, Jaesang
如何在发育中的神经系统中维持未分化的神经祖细胞库是一个尚未解决的问题。这些细胞自我更新的关键转录因子之一是 Sox2，其强制表达已被证明可以抑制体内神经元分化。为了剖析 Sox2 活性的分子机制，对 Sox2 进行了 ChIP-on-chip 检测，并分离了多个候选直接靶基因。在本报告中，我们提供的证据表明，Sox6 与 Sox2 一样属于 SRY 相关的 HMG 盒转录因子家族，是 Sox2 真正的直接调控靶点。在体内，心室区 Sox2 阳性神经前体细胞中 Sox6 的表达存在时间滞后，并且 Sox2 作为转录激活剂促进 Sox6 的表达。有趣的是，功能获得和功能丧失分析表明，Sox6 反过来是维持 Sox2 表达所必需的，这表明这两个转录因子之间存在正反馈环，其作用是抑制神经元过早分化。
How a pool of undifferentiated neural progenitor cells is maintained in the developing nervous system is an issue that remains unresolved. One of the key transcription factors for self-renewal of these cells is Sox2, the forced expression of which has been shown to inhibit neuronal differentiation in vivo. To dissect the molecular mechanisms of Sox2 activity, a ChIP-on-chip assay has been carried out for Sox2, and multiple candidate direct target genes have been isolated. In this report, we provide evidence indicating that Sox6, which like Sox2 belongs to the SRY-related HMG box transcription factor family, is a bona-fide direct regulatory target of Sox2. In vivo, Sox6 expression is seen with a temporal lag in Sox2-positive neural precursor cells in the ventricular zone, and Sox2 promotes expression of Sox6 as a transcriptional activator. Interestingly, gain-and loss-of-function assays indicate that Sox6 in turn is required for the maintenance of Sox2 expression, suggesting that a positive feedback loop, which functions to inhibit premature neuronal differentiation, exists between the two transcription factors.